Asymmetric Myocardial Involvement as an Early Indicator of Cardiac Dysfunction in Pediatric Dystrophinopathies: A Study on Cardiac Magnetic Resonance (CMR) Parametric Mappings.

Dystrophinopathies, such as Duchenne and Becker muscular dystrophy, frequently lead to cardiomyopathy, being its primary cause of mortality. Detecting cardiac dysfunction early is crucial, but current imaging methods lack insight into microstructural remodeling. This study aims to assess the potential of cardiac magnetic resonance (CMR) parametric mappings for early detection of myocardial involvement in dystrophinopathies and explores whether distinct involvement patterns may indicate impending dysfunction. In this prospective study, 23 dystrophinopathy patients underwent CMR with tissue mappings. To establish a basis for comparison, a control group of 173 subjects was analyzed. CMR protocols included SSFP, T2-weighted and T1-weighted sequences pre and post gadolinium, and tissue mappings for native T1 (nT1), extracellular volume (ECV), and T2 relaxation times. The difference between the left ventricular posterior wall and the interventricular septum was calculated to reveal asymmetric myocardial involvement. Significant differences in LV ejection fraction (LVEF), myocardial mass, and late gadolinium enhancement confirmed abnormalities in patients. Tissue mappings: nT1 (p < 0.001) and ECV (p = 0.002), but not T2, displayed substantial variations, suggesting sensitivity to myocardial involvement. Asymmetric myocardial involvement in nT1 (p = 0.01) and ECV (p = 0.012) between septal and LV posterior wall regions was significant. While higher mapping values didn't correlate with dysfunction, asymmetric involvement in nT1 (ρ=-0.472, p = 0.023) and ECV (ρ=-0.460, p = 0.049) exhibited a significant negative correlation with LVEF. CMR mappings show promise in early myocardial damage detection in dystrophinopathies. Although mapping values may not directly correspond to dysfunction, the negative correlation between asymmetric involvement in nT1 and ECV with LVEF suggests their potential as early biomarkers. Larger, longitudinal studies are needed for a comprehensive understanding and improved risk stratification in dystrophinopathies.

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype−phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype−phenotype correlations and improve prognostic outcomes.

Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy.

X-linked myotubular myopathy (XLMTM) is a severe form of centronuclear myopathy, characterized by generalized weakness and respiratory insufficiency, associated with pathogenic variants in the MTM1 gene. NGS targeted sequencing on the DNA of a three-month-old child affected by XLMTM identified the novel hemizygous MTM1 c.1261-5T>G intronic variant, which interferes with the normal splicing process, generating two different abnormal transcripts simultaneously expressed in the patient's muscular cells. The first aberrant transcript, induced by the activation of a cryptic splice site in intron 11, includes four intronic nucleotides upstream of exon 12, resulting in a shift in the transcript reading frame and introducing a new premature stop codon in the catalytic domain of the protein (p.Arg421SerfsTer7). The second aberrant MTM1 transcript, due to the lack of recognition of the 3' acceptor splice site of intron 11 from the spliceosome complex, leads to the complete skipping of exon 12. We expanded the genotypic spectrum of XLMTM underlying the importance of intron−exons boundaries sequencing in male patients affected by XLMTM.

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.

Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort.

BACKGROUND: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. OBJECTIVE: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). RESULTS: 27 patients (2-62 years, 21-80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A "COL6-like sandwich sign" was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. CONCLUSION: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.

COVID-19 in children with neuromuscular disorders.

OBJECTIVE: Children with neuromuscular disorders have been assumed to be a particularly vulnerable population since the beginning of COVID-19. Although this is a plausible hypothesis, there is no evidence that complications or mortality rates in neuromuscular patients are higher than in the general population. The aim of this study is to describe the clinical characteristics and outcome of COVID-19 in children with neuromuscular disorders. METHODS: A registry of children with neuromuscular conditions and laboratory-confirmed-SARS-CoV-2 infection was set up by the Neuromuscular Working Group of the Spanish Pediatric Neurology Society (SENEP). Data to be collected were focused on the characteristics and baseline status of the neuromuscular condition and the course of COVID-19. RESULTS: Severe complications were not observed in our series of 29 children with neuromuscular disorders infected by SARS-CoV-2. Eighty-nine percent of patients were clinically categorized as asymptomatic or mild cases and 10% as moderate cases. Patients with a relatively more severe course of COVID-19 had SMA type 1 and were between 1 and 3 years. CONCLUSIONS: The course of COVID-19 in children with neuromuscular disorders may not be as severe as expected. The protective role of young age seems to outweigh the risk factors that are common in neuromuscular patients, such as a decreased respiratory capacity or a weak cough. Further studies are needed to know if this finding can be generalized to children with other chronic diseases.